Dihalopyridines comprise an important group of compounds useful as intermediates in the manufacture of several commercial materials. For example, 2,3-dichloropyridine is an important raw material for the preparation of crop protection agents, pharmaceuticals and other fine chemicals. A need exists for efficient and practical processes for the manufacture of 2,3-dichloropyridine that are environmentally benign.
2,3-Dichloropyridine has been made from 5,6-dichloronicotinic acid by decarboxylation and from 3-amino-2-chloropyridine by diazotization/chlorination. The manufacture of 2,3-dichloropyridine from 3-amino-2-chloropyridine using a modified Sandmeyer reaction approach has also been reported. The Sandmeyer reaction generally requires preparation of a diazonium salt from 3-amino-2-chloropyridine with an alkali nitrite followed by reaction in the presence of a copper(I) or copper(II) salt. Stoichiometric amounts of the copper salts are typically used to provide efficient preparation of the dichloropyridine from the diazonium salt, resulting in the need for costly recovery of expensive and potentially toxic copper by-products from the process waste stream. Additionally, isolation of the 2,3-dichloropyridine is usually accomplished by extraction of the 2,3-dichloropyridine from the reaction mixture with a water immiscible solvent followed by removal of the solvent adding to the amount of waste that must be processed.
A process for the preparation of 2,3-dibromopyridine involving temperature dependent displacement of chloride by bromide during the diazotization of 3-amino-2-chloropyridine, followed by addition of CuBr in 48% HBr resulting in high yields of 2,3-dibromopyridine has been previously disclosed.
Although diazonium salts are usually prepared in a separate step and subsequently added to a mixture containing the copper salt, requiring the accumulation of potentially hazardous amounts of the unstable diazonium salt, the addition of sodium nitrite to a solution of 3-amino-2-chloropyridine containing copper salts leading to 2,3-dichloropyridine has been disclosed.
Several processes for providing the starting material for the Sandmeyer reaction, e.g. 3-amino-2-chloropyridine, have been previously disclosed, including chlorination of 3-amino-pyridine using chlorine or hydrogen peroxide and hydrogen chloride. Formation of 3-amino-pyridine from niacinamide has also been previously disclosed.
A process for the manufacture of dihalopyridines has been discovered that does not require the use of expensive and potentially environmentally harmful copper salts, does not require the use of multiple reaction vessels, and does not require the use of additional solvents for isolation of the dihalopyridine.
In one embodiment of the invention, a process is described for the manufacture of a compound of formula (A)
wherein
X1 and X2 are in each instance independently selected from the group consisting of Cl and Br;
Y represents from 0 to 3 substituents independently selected in each instance from the group consisting of halide, CN, NO2, OH, optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
wherein the process comprises the step of adding a first liquid mixture comprising a metal nitrite salt to a second liquid mixture comprising a compound of formula (B)
a hydrohalic acid, and an iron(III) compound.